4-(aminomethyl)-piperidine benzamides for treating gastrointestinal disorders

Abstract

The present invention of compounds of formula (I) a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof, —R 1 —R 2 — is a bivalent radical of formula wherein in said bivalent radicals one or two hydrogen atoms may be substituted with C 1-6 alkyl or hydroxy; R 3 is hydrogen or halo; R 4 is hydrogen or C 1-6 alkyl; R 5 is hydrogen or C 1-6 alkyl; L is C 3-6 cycloalkyl, oxoC 5-6 cycloalkyl, C 2-6 alkenyl, or L is a radical of formula —Alk—R 6 —, Alk—X—R 7 , —Alk—Y—C(═O)—R 9 , or —Alk—Y—C(═O)—NR 11 R 12 wherein each Alk is C 1-12 alkanediyl; and R 6 is hydrogen, amino, cyano, C 1-6 alkylsulfonylamino, C 3-6 cycloalkyl, oxoC 5-6 cycloalkyl, aryl or a heterocyclic ringsystem; R 7 is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, aryl or a heterocyclic ringsystem; X is O, S, SO 2 or NR 8 ; said R 8 being hydrogen or C 1-6 alkyl; R 9 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyloxy, hydroxy or aryl; Y is a direct bond or NR 10 ; said R 10 being hydrogen, or C 1-6 alkyl; R 11 and R 12 each independently are hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or R 11 and R 12 combined with the nitrogen atom may form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl or 4-morpholinyl ring. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating or preventing gastrointestinal disorders.

What is claimed is:  
     
       1. A compound of formula (I)                    
       a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof, wherein —R 1 —R 2 — is a bivalent radical of formula                    
        wherein in said bivalent radicals optionally one or two hydrogen atoms on the same or a different carbon atom may be replaced by C 1-6 alkyl or hydroxy,  
       R 3  is hydrogen or halo;  
       R 4  is hydrogen or C 1-6 alkyl;  
       R 5  is hydrogen or C 1-6 alkyl;  
       L is C 3-6 cycloalkyl, oxoC 5-6 cycloalkyl, or C 2-6 alkenyl,  
       or L is a radical of formula                    
        wherein each Alk is C 1-12 alkanediyl; and  
       R 6  is hydrogen, cyano, amino, C 1-6 alkylsulfonylamino, C 3-6 cycloalkyl, oxoC 5-6 cycloalkyl, aryl or Het 1 ;  
       R 7  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, aryl or Het 2 ;  
       X is O, S, SO 2  or NR 8 ; said R 8  being hydrogen or C 1-6 alkyl;  
       R 9  is hydrogen, C 16 alkyl, C 3-6 cycloalkyl, C 1-6 alkyloxy, hydroxy or aryl; Y is a direct bond, NR 10 , O, S, O—(CH2) n —, S—(CH 2 ) n —, or —NR 10 —(CH 2 ) n —, wherein n is an integer from 1 to 6, and R 10  being hydrogen or C 1-6 alkyl;  
       R 11  and R 12  each independently are hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or R 11  and R 12  combined with the nitrogen atom bearing R 11  and R 12  may form a pyrrolidinyl or piperidinyl ring both being optionally substituted with C 1-6 alkyl, amino or mono or di(C 1-6 alkyl)amino, or said R 11  and R 12  combined with the nitrogen bearing R 11  and R 12  may form a piperazinyl or 4-morpholinyl radical both being optionally substituted with C 1-6 alkyl; and  
       each aryl represents unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, amino-sulfonyl, C 1-6 alkylcarbonyl, nitro, trifluoromethyl, amino or aminocarbonyl; and  
       Het 1  and Het 2  each independently are selected from furan; furan substituted with C 1-6 alkyl or halo; tetrahydrofuran; tetrahydrofuran substituted with C 1-6 alkyl; dioxolane; dioxolane substituted with C 1-6 alkyl; dioxane; dioxane substituted with C 1-6 alkyl; tetrahydropyran; tetrahydropyran substituted with C 1-6 alkyl; pyrrolidinyl; pyrrolidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, or C 1-6 alkyl; pyridinyl; pyridinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C 1-6 alkyl; pyrimidinyl; pyrimidinyl substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyloxy, amino and mono and di(C 1-6 alkyl)amino; pyridazinyl; pyridazinyl substituted with one or two substituents each independently selected from hydroxy, C 1-6 alkyloxy, C 1-6 alkyl or halo; pyrazinyl; pyrazinyl substituted with one ore two substituents each independently selected from halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyloxy, amino, mono- and di(C 1-6 alkyl)amino and C 1-6 alkyloxycarbonyl;  
       Het 1  can also be a radical of formula                    
       Het 1  and Het 2  each independently can also be selected from the radicals of formula                    
       R 13  and R 14  each independently are hydrogen or C 1-4 alkyl.  
     
     
       2. A compound as claimed in  claim 1  wherein the —OR 4  radical is situated at the 3-position of the piperidine moiety having the trans configuration. 
     
     
       3. A compound as claimed in  claim 1  wherein the —OR 4  radical is situated at the 4-position of the piperidine moiety. 
     
     
       4. A compound as claimed in  claim 1  wherein the compound is: 
       (3S-trans)-4-[[[(8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-yl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinebutanoic acid, a pharmaceutically acceptable acid addition salt or an N-oxide thereof.  
     
     
       5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to  claim 1 . 
     
     
       6. A process for preparing a pharmaceutical composition wherein a therapeutically active amount of a compound according to  claim 1  is intimately mixed with a pharmaceutically acceptable carrier. 
     
     
       7. A process for preparing a compound of formula (I) wherein 
       a) an intermediate of formula (II) is N-alkylated with an intermediate of formula (III) in a reaction-inert solvent and, optionally in the presence of a suitable base,                    
       b) an appropriate ketone or aldehyde intermediate of formula L′=O (IV), said L′=O being a compound of formula L-H, wherein two geminal hydrogen atoms in the C 1-12 alkanediyl moiety are replaced by ═O, is reacted with an intermediate of formula (III);                    
       c) an intermediate of formula (V) is reacted with an carboxylic acid derivative of formula (VI) or a reactive functional derivative thereof;                    
       d) an intermediate of formula (VII), wherein X is bromo or iodo, is carbonylated in the presence of an intermediate of formula (V) in a reaction-inert solvent in the presence of a suitable catalyst and a tertiary amine, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture;                    
       wherein in the above reaction schemes the radicals L, R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 1  and W is an appropriate leaving group;  
       e) or, compounds of formula (I) are converted into each other following art-known transformation reactions; or if desired; a compound of formula (I) is converted into a pharmaceutically acceptable acid addition salt, or conversely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali; and, if desired, preparing stereochemically isomeric forms thereof.  
     
     
       8. A method for treating hypermotility, irritable bowel syndrome (IBS), constipation-predominant IBS, diarrhea-predominant IBS, pain-predominant IBS, non-pain-predominant IBS, bowel hypersensitivity and the reduction of pain associated with gastrointestinal hypersensitivity and/or hyperactivity comprising administering an effective amount of a compound according to  claim 1 . 
     
     
       9. A compound of formula (III)                    
       a pharmaceutically acceptable acid addition salt thereof or a stereochemically isomeric form thereof, wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 1 .